Our long term goal is to establish animal models for human influenza infection, pathogenesis, transmission and evolution. There is particular concern about the possibility that avian influenza viruses of the H5N1 subtype could lead to a pandemic. These viruses are transmitting directly from birds to humans, although they have been unable yet to maintain sustained human-to-human transmission. We propose to study the mechanisms that avian influenza viruses require to infect mammals as well as the potential evolution of those viruses to transmit human-to-human which is required to cause a pandemic. The molecular basis for the efficient transmission of influenza viruses from among humans is not well understood, although the aerosol transmission is known to be important in the process. With the emergence of direct transmission of influenza viruses from avian species to humans but little human-to-human transmission, it is crucial to determine the genetic traits that lead to efficient transmission of potentially pandemic viruses in humans. We propose two specific aims to address: 1) The transmissibility potential of human H1, H2, and H3 viruses as well as avian H5, H7, and H9 viruses that have been implicated in bird-to-human infections. We will determine the effect of particle size for efficient aerosol spread and the effect that virus morphology has to establish a natural chain of transmission in the ferret model. We will compare the effect of influenza infections in two animal model systems, the ferret and the cotton rat, both of which can display typical flu symptoms without requiring virus adaptation. We will use unrestrained whole body plethysmography to determine the frequency of respiration, airway responsiveness (ratio of inspiration to expiration) and time between breaths and compare them with the effect of aerosolization of influenza virus particles. We will study virus survival in sputum samples of infected ferrets to better understand the natural conditions that might affect the stability of the virus and its effect for efficient transmission. 2) We will generate avian/human reassortant influenza viruses by reverse genetics or by co-infection of ferrets with an avian and a human strain to determine whether such reassortants are viable and better define the factors that control transmission of avian influenza viruses in this animal model system.